Imipenem is a broad spectrum β-lactam antibiotic, belonging to the group carbapenems. It is derived from a compound called thienamycin of formula (II).

Imipenem and the process for its preparation are described in U.S. Pat. No. 4,194,047 patent, in which the process involves lyophilization. Methyl formimidate was reacted with thienamycin in the process for the preparation of N-formimidoylthienamycin (Imipenem).
U.S. Pat. No. 4,260,543 patent describes crystalline Imipenem monohydrate. According to this patent, crystalline Imipenem monohydrate is prepared by dissolving N-formimidoylthienamycin in water followed by diluting the said solution with ethanol to yield crystalline N-formimidoylthienamycin monohydrate (Imipenem) crystals. This patent provides the technique of crystallization of Imipenem in aqueous medium by the addition of an organic solvent.
U.S. Pat. No. 4,374,772 patent describes a process for preparing Imipenem by reacting thienamycin with benzyl formimidate as shown in reaction scheme-1.

The reagent benzyl formimidate utilized in the preparation of Imipenem is obtained by reacting formamide (such as dibutylformamide or dimethyl formamide), benzyl alcohol and benzoyl chloride in a solvent selected from 2-methyltetrahydrofuran, tetrahydrofuran, diethyl ether, isopropyl ether, sulfolane, dioxane and the like, preferably, 2-methyltetrahydrofuran; in the presence or absence of catalyst selected from (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo 1,2-C or tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-C][1,3,2]oxazaborole-borane complex or (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-C][1,3,2]oxazaborole-borane complex at a temperature in the range of −25° C. to −20° C. The product was recovered by the addition of acetic anhydride according to the literature available in the prior art.
U.S. Pat. No. 4,616,038 patent provides a process for the crystallization of N-formimidoylthienamycin by adding ethanol to a concentrated solution of N-formimidoylthienamycin. This patent provides a method for isolating Imipenem monohydrate directly from the reaction solution with out using lyophilization method.
US 2002/0095034 describes a process for the preparation of Imipenem by activating (3R,5R,6S)-2-oxo-6-[(1R)-1-hydroxyethyl]carbapenem-3-carboxylic acid p-nitrobenzyl ester with diphenylphosphorohydrochloride followed by reacting the activated compound with cysteamine hydrochloride in the presence of a base to produce thienamycin p-nitrobenzyl ester hydrochloride in the form of N-methylpyrrolidinone solvate, which is further reacted with alkyl formimidate to produce Imipenem p-nitrobenzyl ester, followed by deprotection to produce Imipenem.
U.S. Pat. No. 7,241,885 B2 patent (Indian patent application number: 595/DEL/2001) provides a process for the preparation and isolation of pure crystalline Imipenem monohydrate by crystallizing Imipenem monohydrate from a solution thereof which contains an organic solvent, aqueous solvent, or a mixture thereof, without using lyophilization.
Process for the preparation of crystalline Imipenem monohydrate is described in U.S. Pat. No. 7,078,534 B2 patent (Indian patent application number: 983/DEL/2000), wherein dianion chromatography is used prior to crystallization of Imipenem monohydrate.
US 2005/004359 A1 (Indian patent application number: 1152/DEL/2001) describes a process for the preparation of crystalline Imipenem monohydrate which comprises: (a) dissolving crude Imipenem monohydrate in warm water in the presence of base; (b) subjecting the resultant solution to activated carbon treatment; and (c) adding an organic solvent to precipitate Imipenem monohydrate as a crystalline product. Due to less solubility of Imipenem monohydrate in water this patent provides a method to dissolve Imipenem monohydrate in water at higher temperature (45-60° C.) in the present of base. At high temperature and pH chances are there for the degradation of Imipenem.
Freeze-crystallization of Imipenem is reported in Journal of Pharmaceutical Sciences 1996, 85(2), 174-177. Solutions containing Imipenem and sodium bicarbonate were crystallized from acetone-water solvent system.
The above processes either use freeze-crystallization or lyophilization or chromatography or reverse osmosis, which are not viable for industrial scale-up process.
Color of the reconstituted solution is an important indicator that indicates stability of the product. The formation of intense color like dark brown, black or reddish brown indicates the presence of highly unsaturated, intensely colored impurities and/or degradation products. A significant change in color of the reconstituted solution can become a limiting factor to the shelf life of a parenteral product. In order to get rid of colored impurities, the prior art patents utilize column chromatographic techniques or treatment with activated carbon.
With our continued research for developing a process for the preparation of compound of formula (I), we have identified a process, in which Imipenem monohydrate was dissolved in the presence of suitable inorganic salt, and yielded the to final compound in good quality.